Sickle cell disease (SCD) and b-thalassemia together comprise the most commonly inherited diseases in man. The only current therapy for SCD is treatment with hydroxyurea (HU). HU induces fetal hemoglobin (HbF) synthesis in about half of treated patients by as yet unknown mechanism(s), and its long term effects are largely unknown. HbF induction is known clinically to reduce organ morbidity and pain in SCD patients, and to inhibit sickle polymer formation and consequently destruction of erythrocytes in vitro. For the past decade, my lab has studied a fetal g-globin gene repressor called DRED. We recently reported the subunit composition of DRED, which is composed of at least four distinct epigenetic modifier co-repressor multiprotein complexes. One of the modifying enzymes is LSD1, a monoamine oxidase that removes activating chromatin signatures, thereby leading to gene repression. We recently tested a highly specific inhibitor for LSD1 called tranylcypromine (TC). We found that in human CD34+ hematopoietic stem cells induced to differentiate into erythroid cells in vitro, HbF was induced to therapeutic levels in a TC dosage-dependent manner. We have filed a novel use patent for TC, which is already FDA approved and off patent, and intend to test for cryptic properties (HbF induction) in cells and sickle cell mice. Should these preliminary tests be fruitful, we will in the future then initiate clinical trials in ealthy and sickle cell patients.

Public Health Relevance

Hemoglobinopathies are the most common inherited disorders in man. Correlative clinical evidence suggests that g-globin replacing bS globin in sickle red cells is therapeutic for SCD. A feasibly attractive strategy to induce g-globin synthesi would be to inactivate a regulatory protein that normally functions to repress g-globin synthesis in adult erythroid precursor cells. We recently identified the enzyme LSD1 as one of the components of a core g-globin repressor complex. Most recently, we discovered that in human CD34+ hematopoietic stem cells induced to differentiate into erythroid cells, reduction of intracellular LSD1 activity via LSD1 mRNA degradation or inhibition of LSD1 catalytic action led to dramatic induction of fetal hemoglobin levels ex vivo. This proposal explores the initial hypothesis that Parnate, an FDA-approved antidepressant, could be used to treat SCD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HL114368-01
Application #
8319822
Study Section
Molecular and Cellular Hematology (MCH)
Program Officer
Hanspal, Manjit
Project Start
2012-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$233,250
Indirect Cost
$83,250
Name
University of Michigan Ann Arbor
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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